1u3s: Difference between revisions
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'''Crystal Structure of Estrogen Receptor beta complexed with WAY-797''' | '''Crystal Structure of Estrogen Receptor beta complexed with WAY-797''' | ||
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[[Category: Miller, C P.]] | [[Category: Miller, C P.]] | ||
[[Category: Xu, Z B.]] | [[Category: Xu, Z B.]] | ||
[[Category: | [[Category: Agonist]] | ||
[[Category: | [[Category: Er]] | ||
[[Category: | [[Category: Er-beta]] | ||
[[Category: | [[Category: Estrogen]] | ||
[[Category: | [[Category: Estrogen receptor]] | ||
[[Category: | [[Category: Estrogen receptor beta]] | ||
[[Category: | [[Category: Nuclear receptor]] | ||
[[Category: | [[Category: Transcription factor]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 10:43:40 2008'' | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 10:43, 3 May 2008
Crystal Structure of Estrogen Receptor beta complexed with WAY-797
OverviewOverview
New diphenolic azoles as highly selective estrogen receptor-beta agonists are reported. The more potent and selective analogues of these series have comparable binding affinities for ERbeta as the natural ligand 17beta-estradiol but are >100-fold selective over ERalpha. Our design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERbeta cocrystallized with various ligands as well as molecular modeling studies. These strategies enabled us to take advantage of a single conservative residue substitution in the ligand-binding pocket, ERalpha Met(421) --> ERbeta Ile(373), to optimize ERbeta selectivity. The 7-position-substituted benzoxazoles (Table 5) were the most selective ligands of both azole series, with ERB-041 (117) being >200-fold selective for ERbeta. The majority of ERbeta selective agonists tested that were at least approximately 50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERbeta-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.
About this StructureAbout this Structure
1U3S is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor-beta ligands., Malamas MS, Manas ES, McDevitt RE, Gunawan I, Xu ZB, Collini MD, Miller CP, Dinh T, Henderson RA, Keith JC Jr, Harris HA, J Med Chem. 2004 Oct 7;47(21):5021-40. PMID:15456246 Page seeded by OCA on Sat May 3 10:43:40 2008